The overall goal of this project is to improve the survival and quality of life of patients with pancreatic and biliary tract carcinoma using photodynamic therapy (PDT). This clinical project involves a number of phase I and III studies using two different photosensitizers (PS), and derives from experimental and early clinical studies of PDT in pancreatic and biliary tract malignancies by our group. In addition, new means for non- invasively measuring PS concentrations and light transmission within tissue will be usedto provide monitoring information that could ultimately be used to manipulate PDT in real time and produce a more effective and uniform therapeutic outcome. The overall theme of the hypotheses tested here is that a reduction in tumor burden can be achieved safely with PDT, and will lead to improvements in survival and quality of life of patients with pancreatic and biliary tract cancer. In Aim 1, following on from our recently completed phase II study of porfimer sodium PDT in biliary tract carcinoma (ETC), a phase III study of palliative PDT plus stenting vs. stenting alone will be performed in patients with locally advanced or metastatic BTC. Aim 2 will test the feasibility and safety of neoadjuvant PDT using porfimer sodium in patients undergoing attempted curative surgical resection of proximal biliary tract carcinoma, with the goal of improving RO resection rates and overall survival. Accurate techniques for dosimetry with photosensitizer and structural treatment planning will also be developed, with the aims of improving PDT dose accuracy and prediction of effect in biliary tract cancer. In Aim 3, in a standard phase I/II dose ranging study using a single fiber followed by a non-randomized phase II multiple fiber study, verteporfin PDT will be administered to patients with locally advanced pancreatic carcinoma to identify the treatment parameters with which to achieve safe and effective tumor necrosis. The results of this study will then be used to inform Aim 4, a randomized phase ll/lll study of verteporfin PDT + standard chemotherapy vs. chemotherapy alone for locally advanced pancreatic cancer. This latter trial will involve full light dose treatment planning with implantation of multiple diffusing fibers into the prescribed volume. The completion of these aims will test the clinical hypotheses that PDT can be successfully incorporated into pancreatobiliary cancer management as a combination approach, either adjuvant or neoadjuvant. Potential benefits to public health: this study with 4 clinical trials could provide new treatments for two cancers, PanCa and BTCwhich currently have few treatment options and are usually fatal putting a heavy burden on society in terms of cost and suffering.